Soumya Swaminathan MD, National Institute for Research in TB (formerly Tuberculosis Research Centre), Chennai
Tuberculosis in India
Accounts for > 25% of global TB burden 2 million new cases, 1.5 million in RNTCP ~ 1000 deaths/day ~ 60% adults latently infected with M.tuberculosis ~ 100,000 MDRTB cases each year 90,000 notified pediatric cased (7% of total) Major risk factors
Undernutrition HIV Diabetes mellitus Smoking, indoor air pollution
In India, among new TB cases, INH resistance 11-17%, MDRTB 2-3% Among re-treatment cases, INH resistance 25-40% and MDRTB 15-20%
Phase III
Cure at end of treatment (bacteriologic) Recurrence (bacteriologic) Death usually low in HIV negative patients Development of drug resistance esp Rifampin Radiographic changes unreliable
Intensive phase
INH RIF
Continuation phase
PZA EMB
92%
94%
96%
97%
Relapse after treatment (up to 24 months) (341 patients with drug susceptible TB)
Ind J Tub 2002: 49: 27-38
Efficacy and Tolerability of 3- and 4- month regimens containing Moxifloxacin in sputum smear and culture positive pulmonary TB
Randomized, parallel group, multiple arm, open label trial (phase III) Intervention: 4 regimens containing Moxifloxacin Outcomes: Relapse (24 months after completion of treatment), sputum culture conversion at 2nd month, bacteriologic response at end of treatment, adverse reactions Period: 2007-2015, sample size 1650 Site and sponsor: Tuberculosis Research Centre, ICMR
Regimens
Regimen 1 Test Reg 1 Test Reg 2 Test Reg 3 Test Reg 4 Control Months 2 3 RHZEM 4 5 6 3 RHM 4 4 4 6 Month s
RHZEM
RHZE3
RH3
P 0.06
P 0.001
STREAM Trial: The Evaluation of a Standardised Treatment Regimen of AntiTuberculosis Drugs for Patients with MDR-TB
Based on short Bangladesh regimen tried under operational/program conditions 4 countries: Ethiopia, India, S Africa, Vietnam Test regimen: moxifloxacin, clofazimine, ethambutol and pyrazinamide given for nine months (40 weeks), supplemented by kanamycin, isoniazid and prothionamide in the first four months (16 weeks). Total max length: 48 weeks Control regimen: Locally used WHO-approved MDRTB treatment regimen Primary Outcomes: proportion of patients with a favourable outcome at 27 months and proportion of patients experiencing Grade III or IV AE
300 patients, ART-nave, 70% PTB, median CD4 count 150 Cure rate and mortality no different Recurrences (bacteriologic) significantly lower with 9-month regimen All 19 patients developed acquired Rifampicin resistance at time of failure
Am J Respir Crit Care Med 2010; 181:743-51
Baseline and recurrence cultures fingerprinted using IS6110, MIRU-VNTR and spoligotyping 20 paired HIV+ and 25 HIV- TB patient specimens Re-activation accounted for 92% of HIV Re-infection accounted for 88% of HIV+ recurrences
J Infect Dis 2010; 201:691-703
Predictors and Immunologic Characterization of TB-associated IRIS in a cohort of HIVinfected TB patients in Chennai
Objectives: To identify clinical and laboratory predictors of tuberculosis-associated IRIS (TB-IRIS) To study the immunopathogenesis of TB-IRIS among HIV-infected patients initiating anti-TB and anti-retroviral trt
NIH Intramural-to-India Program/US-India JWG Collaborators: Tuberculosis Research Centre, Chennai, India (Soumya Swaminathan, G Narendran, Subhash Babu) NIH/NIAID/LIR & LPD, Bethesda, Maryland (Brian Porter, Irini Sereti, Alan Sher)
Safety and Efficacy of two different oncedaily antiretroviral treatment regimens along with anti-TB treatment
Randomized, open label, active control, parallel assignment safety/efficacy trial Interventions: ddI/3TC/NVP vs ddI/3TC/EFV along with standard intermittent TB regimen, from 2nd month of ATT Outcome: virological suppression at 6 months, adverse events, death, TB cure/relapse 2006-2009, sample size 180 Site: Tuberculosis Research centre clinics at Chennai, Madurai and Vellore, Tamil Nadu Sponsor: National AIDS Control Organization
Nevirapine regimen N = 57
38 (67%) 19 11
Favourable response
(viral load < 400 copies/ml)
death
Lost to f/u
5
3
Efficacy of a Six-month vs a 36-month regimen for prevention of tuberculosis in HIV-infected persons in India: A Randomized Clinical Trial Randomized, open label clinical trial Interventions: 6EH vs 36H Endpoint: development of TB, death, AE Period: 2001-2008 Site: Tuberculosis Research centre clinics at Chennai, Madurai Sponsor: USAID through WHO In press Plos One
Results
712 patients randomized, 2/3rds female, median CD4 count 350 TB Incidence rate (2.4 and 1.5/100 py) much lower than historical 6.9/100py both regimens highly efficacious in preventing TB No significant difference between 6EH and 36H in efficacy or safety TB and death rates 3-4 times higher in CD4<200 group, regardless of regimen Both regimens equally effective in TST+ and TST- individuals
TB Incidence Rate
6EH 36H
Rate Ratio
Cost-Effectiveness Results
Life expectancy Strategy (years) Costs ($) Selective 16.85 95 referral Current 16.86 110 standard Routine 16.88 120 referral
India per capita GDP: $1,015
Early vs Delayed initiation of ART for Indian HIV-Infected individuals with TB on ATT
Randomized, open label trial 150 HIV+ TB+ randomized to receive ART (d4T / ZDV + 3TC + EFV) after 2-4 or 8-12 weeks of starting ATT Primary end points: death from any cause & progression of HIV disease No difference in mortality in groups Incidence of ART failure was 31% in delayed versus 16% in early ART arm (p = 0.045) KM - Disease progression free Sinha et al, BMC Infectious Diseases 2012, 12:168 doi:10.1186/1471-2334survival 12-168
At 79%, significantly better for the early ART group, as against 64% for delayed ART group (p = 005)
Immediate versus delayed start of anti-HIV therapy in HIV-infected TB patients with CD4< 250 cells/mm3 (ACTG 5221) N Engl J Med 2011;365:1482-91.
Immediate (within 2 weeks) ART compared to deferred ART (after 8 weeks) of ATT in reducing death and AIDSdefining illness Randomized, open label, active control, parallel assignment, safety/efficacy study TDF/FTC/EFV orally once daily within 2 weeks or at 812 weeks of ATT in patients with CD4 < 200 cells/mm Outcome: proportion of patients surviving without AIDS progression at week 48 Period: 2006-2013, SS 800 Site: multicentric, 22 sites globally. YRG Care, Chennai Sponsor: NIAID, NIH
Efficacy and Safety of Immunomodulator as an Adjunct Therapy in New Pulmonary TB (Cat I) Patients
Randomized double blind placebo controlled safety/efficacy study (Phase III) 6 doses of Mycobacterium indicus pranii 0.1 ml (100 million bacilli) intradermal Time of sputum conversion and cure rate, relapses and clinical adverse events Period: 2007-2009, sample size 300 Multicentric Sponsor: Dept of Biotechnology, Govt of India Data under analysis
Efficacy of Oral Zinc Administration as an Adjunct Therapy in New Pulmonary TB (Cat I) Patients
Randomized double blind placebo controlled parallel assignment efficacy trial Role of oral zinc (50mg/day) along with ATT among newly diagnosed pulm TB pts 2008-2009, sample size 150 Time of smear conversion, cure rate, relapses, adverse reactions and immunological changes Site: AIIMS, New Delhi Sponsor: Ministry of Science and Technology
Role of N-acetyl cysteine in patients with newly detected sputum positive pulm TB
Randomized, parallel group placebo controlled trial Intervention: N-acetyl cysteine 600mg once daily vs placebo, along with standard ATT Outcome: sputum smear conversion rate (1, 2, 4, 6 month), cure and relapse rates Period: 2007-2009, SS 60 Site and sponsor: Christian Medical College, Vellore
Protective effect of curcumin, silymarin and Nacetylcysteine on antitubercular drug-induced hepatotoxicity in an in vitro model
Hum Exp Toxicol. 2012 Aug;31(8):788-97
Aim: to investigate the role of curcumin (CUR), silymarin (SILY) and N-acetylcysteine (N-ACET) on hepatotoxicity by ATT drugs using an in vitro model of human hepatocellular carcinoma cell line (HepG2) Results: (a) increased cell viability, (b) healthy-looking cell morphology as revealed by phase contrast microscopy, (c) active respiring cells as observed with confocal microscopy upon staining with a mitochondrial membrane-specific dye, MitoTracker() Red, and reduction in the sub-G(1) peak in cell cycle analysis by flow cytometry Clinical trials needed
Hum Exp Toxicol. 2012 Aug;31(8):788-97. doi: 10.1177/0960327111433901. Epub 2012 Feb 8. Singh M, Sasi P, Gupta VH, Rai G, Amarapurkar DN, Wangikar PP. Source Department of Chemical Engineering, Indian Institute of Technology Bombay, Powai, Mumbai, Maharashtra, India.
Efficacy and Safety of Modified Anti-tubercular Regimens in Treatment of Tuberculosis in Patients With Underlying Compensated and Decompensated Chronic Liver Disease
This study is not yet open for participant recruitment. Verified August 2012 by Institute of Liver and Biliary Sciences, India Sponsor: Institute of Liver and Biliary Sciences, India ClinicalTrials.gov Identifier: NCT01677871 Study Type Interventional Study Phase Study Design Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment Condition Chronic Liver Disease With Tuberclosis Intervention
Drug: 2HRZE/4HRIsoniazid + Rifampicin+Pyrazinamide+Ethambutol for initial 2 months followed by Isoniazid + Rifampicin for next 4 months
Drug: 2HRLE/4HRIsoniazid + Rifampicin+ Levofloxacin+Ethambutol for initial 2 months followed by Isonizid + Rifampicin for next 4 months Drug: 9HLEIsoniazid+ Levofloxacin+ Ethambutol for 9 months Drug: 9RLERifampicin + Levofloxacin+ Ethambutol for 9 months Study Arm (s)
Experimental: 2HRZE/4HRIsoniazid + Rifampicin+Pyrazinamide+Ethambutol for initial 2 months floolowed by Isoniazid + Rifampicin for next 4 monthsIntervention: Drug: 2HRLE/4HR
Active Comparator: 2HRLE/4HRIsoniazid + Rifampicin+ Levofloxacin+Ethambutol for initial 2 months followed by Isonizid + Rifampicin for next 4 monthsIntervention: Drug: 2HRZE/4HR Experimental: 9HLEIsoniazid+ Levofloxacin+ Ethambutol for 9 monthsIntervention: Drug: 9RLE Active Comparator: 9RLERifampicin + Levofloxacin+ Ethambutol for 9 monthsIntervention: Drug: 9HLE
Safety and Efficacy of different regimens of reintroduction of anti-TB drugs in anti-TB drug induced liver damage
Randomized open label, dose comparison, parallel assignment safety/efficacy study At time of re-introduction of anti-TB drugs, patients randomized to i) daily INH, Rif, PZA full dose ii) Rif day 1, INH day 8, PZA day 15 full dose iii) gradually increasing doses of INH day 1, Rif day 8 and PZA day 15 Safety, predictors and risk factors for recurrence Liver functions monitored weekly Period: 2006-2008 Sites: Tirupati, AP and New Delhi Sponsor: All India Institute of Medical Sciences, N Delhi
Early bactericidal activity and pharmacokinetic study of LL 3858 among newly diagnosed sputum smear positive pulmonary TB patients
Phase IIa open label single arm study to determine EBA, extended EBA and pharmacokinetics of novel compound LL 3858 of Lupin Ltd Intervention: LL3858 400 mg OD orally for 5 days. 16 hr collection of sputum on day 1,3,4,6 Patients will receive full ATT from day 7 Outcome: Safety, fall in log10 colony forming units (CFU) of M.tuberculosis/ml sputum 0-2 days (EBA) and 2-5 days (extended EBA), PK profile full profile after 1st and 5th dose and a sample on days 7 and 8 Sample size: 40 (20 analyzable) Period: 2009 (not yet recruiting) Sponsor: Lupin Ltd
Research Priorities
Efficient and cost-effective point of care diagnostic test for TB (all forms) Shorter treatment regimens for drugsusceptible and drug resistant TB Trials of new and repurposed drugs for TB Adjunct treatment with agents that improve drug efficacy/tolerability Pharmacokinetics of first and second line anti-TB drugs in adults and children Effective TB vaccine